Tremor is a relatively treatment-resistant symptom of various movement disorders, for example Parkinson's disease (PD) and Essential Tremor (ET), and Essential Tremor is one of the most common movement disorders. Tremor is assumed to be visually easy to assess and therefore should be relatively easy to treat ET action tremors (postural or kinetic) and PD rest tremors. However, detailed kinematic assessment of both tremor types to deconstruct tremor dynamics, including both muscle composition and directional bias have not been done to validate these assumptions.
Although tremor in ET and PD can involve the head, face, and tongue, the most common site remains the limbs, particularly the upper limbs. Subsequent functional impairment is a result of tremor, and this can be substantially disabling if the dominant arm is affected. In PD, tremor symptoms are commonly one-sided while for ET the tremor will be bilateral. In addition, the presence of tremor is an obvious visible symptom, which can be cosmetically disabling, making patients feel as though they “stand out” causing emotionally distress. Due to such functional and psychological disability, an effective treatment method for focal tremor remains an important need in affected individuals. While options exist for management of ET and PD tremor, the therapeutic efficacy can still be quite poor with the side effects of medication and danger in brain surgery pose considerable risk, especially in the older age group.
Botulinum neurotoxin such as type A or B (BoNT A, BoNT B, BTX-A, BTX-B) injection therapy has shown efficacy and is indicated for the management of focal disorders such as cervical dystonia (torticollis), blepharospasm and upper limb spasticity, to name a few. Although tremor has been treated with BoNT A, the studies have been open-label, or small and the results of BoNT A have not generally been particularly favorable. For ET, injection with BoNT A can indeed reduce postural tremor amplitude as measured by accelerometry and clinical rating scales. However, all patients had some degree of weakness as a side effect, and functional disability and action tremor did not improve significantly. It is possible that despite the reduction in tremor, weakness overshadowed the improvement and resulted in a lack of significant functional improvement seen. Nevertheless, chemodenervation with BoNT A appears to be a viable option for treatment of ET. However, this has not been largely accepted as a primary treatment option by clinicians, approved by health regulatory bodies, nor is it reimbursed by insurance companies for off-label use.
The lack of functional improvement using BoNT A is a side effect profile produced by the injection. Intramuscular injections can produce substantial weakness in the muscles due to the toxin's well-known action. This weakness is in the muscles injected and also in the adjacent muscles due to the spread of the toxin. It is known that this weakness and spread is dose and volume dependent. However, the most significant determinant of this side effect may be the selection of the appropriate and most responsible muscles that contribute to the tremor seen and the dosage injected within the muscles, and not to inject non-contributing muscles. The most important component of muscle selection is the clinician's ability to determine the predominant direction of movement of the affected body part. This is true even for dystonia and spasticity, the two other syndromes where BoNT A is successfully used. In these conditions, the movement can be generally fairly stereotyped and the predominant postures of the body parts affected can be visually assessed by the clinician. However, when tremor is superimposed on say cervical dystonia, the assessment of the movement and the subsequent injection pattern determination becomes that much more difficult.
To date, the tremor of PD and ET have been assumed to having well established “clinical features”: rest tremor in PD and postural and kinetic tremor in ET. Additionally, the predominant composition of these tremor types has been also assumed to be flexion/extension, mainly present at the wrist. Finally, despite the complexity of such tremors, the judgment of which muscles to inject and the dosage of BoNT A required is achieved purely on visual inspection, different for each patient. Tremor in the upper limb can be complex to assess visually simply because of the number of body parts involved. Traditionally tremor has been associated at the wrist joint and fingers, however, our findings show the tremors are present often at the shoulder, elbow, wrist, and in fingers. In addition, each of these joints has many degrees of freedom in terms of movement. The wrist can flex and extend, and show ulnar and radial deviation, while at the same time the elbow may show pronation-supination and flexion-extension. The shoulder can also flex-extend and have abduction-adduction movements. Such multidimensional motion is then summed in producing the actual tremor. The clinician has to then visually decompose these components and then determine the relative contributions of each in order to estimate which muscle groups to select for injection. In most cases this is a very difficult task and may over- or under-estimate the movement subcomponents. If this happens, the injections of BoNT A may be given in incorrect muscle groups resulting in suboptimal benefit and increased side effects.
Thus, there is a need in the art for methods that better assess tremor composition.